Hepatocellular carcinoma: recent advances and emerging medical therapies

Introduction

Among all cancers globally, liver cancer ranked the sixth in incidence and the fourth in mortality, accounting for 841,080 new cases and 781,631 deaths worldwide in 2018 ¹. Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer, with risk factors including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection as well as cirrhosis of any etiology such as alcoholic liver disease, non-alcoholic steatohepatitis, and primary biliary cholangitis. Diagnosis of HCC is usually made by contrast enhanced imaging. Barcelona Clinic Liver Cancer (BCLC) staging remains the most commonly used staging system ^{2, 3}. BCLC staging incorporates tumor burden, liver reserve, and performance status and classifies HCC into very early stage (0), early stage (A), intermediate stage (B), advanced stage (C), and terminal stage (D) ⁴. The management strategy can then be recommended according to different stages of disease ². Recently, a popular staging system, the Hong Kong liver cancer staging system (HKLC), which is derived from a group of Hong Kong experts ⁵, was introduced. According to this study, it has a better discriminating power than BCLC ⁶. Nevertheless, it is noteworthy that BCLC is derived from mostly HCV-related HCC cases, while HKLC is derived from an Asian cohort where HBV is the predominant risk factor for HCC. Surgical resection, tumor ablation, and liver transplantation are curative treatments indicated for very early and early stage HCC. Owing to a lack of widely implemented HCC surveillance programs in many parts of the world, most patients are unfortunately diagnosed at an advanced stage, precluding curative therapy ⁷.

Non-surgical management for HCC includes locoregional intra-arterial therapy, systemic treatment with multi-kinase inhibitors, and immunotherapy. Recent advances and emerging strategies in these modalities to improve the outcome of HCC will be reviewed.

Intra-arterial therapy

Multi-kinase inhibitors

Tumor cell proliferation, differentiation, and angiogenesis are postulated to be mediated by multiple intracellular and cell surface protein kinases with their downstream pathways, as depicted in Figure 1 ²⁴. Sorafenib, an inhibitor of platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), rearrange during transfection (RET), and C-kit, is the first multi-kinase inhibitor proved to be beneficial in unresectable, advanced-stage HCC. The SHARP trial is the first phase III, placebo-controlled trial of the use of sorafenib in HCC. In this landmark study involving 602 patients with advanced disease naïve to systemic treatment, median OS was significantly improved in the sorafenib group compared to the placebo group (10.7 versus 7.9 months, P <0.001) ²⁵. Another multi-national randomized controlled trial in the Asia-Pacific region, where chronic hepatitis B is the major risk factor for HCC, also confirmed the findings in the SHARP study ²⁶. Further analysis of the two randomized controlled trials identified HCV-related HCC, absence of extrahepatic spread, and low neutrophil-to-lymphocyte ratio as predictors of greater survival benefit with sorafenib ²⁷. The remarkable result with sorafenib is considered a major breakthrough in more than 30 years of pursuing a systemic treatment for HCC. However, the therapeutic window is narrow with sorafenib, with restrictions to patients with good performance status and compensated cirrhosis. Also, dose-limiting side effects including hand-foot-skin reaction, diarrhea, and weight loss are not uncommon. However, recent studies have shown an association between dermatological adverse effects with sorafenib with better treatment outcomes ^{28, 29}. Over subsequent years, other agents have been studied as alternative first-line treatments against sorafenib or as second-line treatments against placebo in patients intolerant to or who have progressed while on sorafenib. Sunitinib, brivanib, linifanib, everolimus, and tivantinib were unable to meet their respective study end points as either non-inferior or superior to sorafenib or show survival benefit in those who failed sorafenib ^{30– 34}.

Lenvatinib, an inhibitor of epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), VEGFR, PDGFR, RET, and C-kit, emerged almost a decade after sorafenib as an alternative first-line treatment for advanced HCC. Non-inferiority to sorafenib in terms of OS (13.6 versus 12.3 months, 95% confidence interval [CI] 0.79–1.06) was demonstrated in the REFLECT trial ³⁵. In patients who progressed while on sorafenib, regorafenib and cabozantinib prolonged survival in their respective phase III randomized controlled trials ( Table 2). Bruix et al. demonstrated that regorafenib treatment resulted in longer median survival than placebo (10.6 versus 7.8 months; hazard ratio [HR] 0.63, P <0.001) ³⁶. Comparable improvement in median OS was shown with cabozantinib by Abou-Alfa et al. (10.2 versus 8.0 months; HR 0.76, P = 0.005) ³⁷. The recombinant IgG1 monoclonal antibody ramucirumab, which inhibits type 2 VEGFR-mediated angiogenesis, is the latest approved agent for advanced HCC. The initial REACH trial using ramucirumab failed to demonstrate benefit over placebo in patients with BCLC stage B and C disease not amenable to locoregional therapy and treated with first-line sorafenib ³⁸. However, the effect of ramucirumab was noted to correlate with baseline AFP level, and benefit in OS was seen in the subgroup of patients with baseline AFP concentration above 400 ng/ml. The finding formed the basis of the follow-up REACH-2 trial, in which only sorafenib-treated patients with baseline serum AFP concentration over 400 ng/ml were recruited. Median OS (8.5 versus 7.3 months; HR 0.71, P = 0.020) and progression-free survival (PFS) (2.8 versus 1.6 months; HR 0.45, P <0.001) were significantly improved in the ramucirumab group compared with the placebo group ³⁹. The study also highlighted that HCC is a heterogeneous disease and that stratification with biomarkers such as AFP is important in the future development of cancer therapy.

Immunotherapy

The past decade has witnessed major breakthroughs in cancer immunotherapy, which has demonstrated benefit in various solid organ and hematological malignancies ⁴⁰. HCC develops in an inflammatory milieu, and immune tolerance is reported to play an important role in tumor pathogenesis ^{41, 41}. Immune checkpoint inhibitors (ICPIs) targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathway are the two most studied immunotherapy mechanisms in HCC ( Figure 1). The two pathways are believed to act at different stages of the immune response. The PD-1/PD-L1 pathway promotes immune tolerance by suppressing the activity of T cells and mediating the differentiation of regulatory T cells, while the CTLA-4 pathway prevents autoimmunity by inhibiting the proliferation of potential autoreactive T cells ^{43, 44}. By inhibiting these immune checkpoints, self-tolerance to malignant cells is lost, resulting in immune-mediated clearance of tumor tissue.

Combination of therapies of different mechanisms

Investigators have brought together locoregional therapy with systemic therapy or systemic therapy of different classes with the hope of augmenting tumor response. The initial experience with adding sorafenib or other molecular targeted therapy to TACE was disappointing ⁵⁴. Inadequate dose and duration of sorafenib in these trials were identified as key reasons for failure. The Japanese TACTICS trial eventually demonstrated superiority of TACE plus sorafenib over TACE alone in terms of longer PFS (25.2 versus 13.5 months, P = 0.006) and longer time to TACE untreatable progression (26.7 versus 20.6 months, P = 0.020) ²². The SORAMIC study looked into the combination of sorafenib and SIRT with Y90 compared with sorafenib alone for advanced HCC. The primary endpoint of OS was not met, but subgroup analysis of non-cirrhotic patients or patients aged under 65 years did show a survival benefit with combination therapy ²³. Future trials should address issues such as timing of sorafenib administration in relation to intra-arterial therapy, patient selection for such combination therapy by balancing potential benefits with incremental adverse effects, and more precise definition of both treatment efficacy and failure.

The combination of atezolizumab, an anti-PD-L1 antibody, and bevacizumab, an anti-VEGF antibody, has been investigated as a first-line systemic therapy in unresectable or metastatic HCC. It is postulated that the anti-angiogenic and immunomodulatory effect of bevacizumab can augment the anti-tumor immune activity of atezolizumab, as shown by a partial response rate of 62% in the phase I trial ⁵⁵. Encouraging results were recently reported from the phase III IMbrave 150 trial comparing the dual therapy with sorafenib, in which statistically significant improvement in both OS and PFS was shown (HR of OS 0.58, P <0.001 and HR of PFS 0.59, P <0.001) ⁵⁶.

Additional phase III trials on combinations of systemic therapies including lenvatinib and pembrolizumab (NCT03713593), cabozantinib and atezolizumab (NCT03755791), sintilimab and IBI305 (NCT0379440), and apatinib and SHR1210 (NCT03764293) are currently ongoing ( Table 2).

Conclusion

HCC remains a deadly disease, and unresectable HCC is associated with limited survival. Considerable advancement in local and systemic therapies has been achieved in recent years owing to better understanding of the tumor microenvironment and the interplay between the tumor and the host immune system. With the latest breakthrough achieved with ICPIs, the armamentarium of treatment for HCC is rapidly expanding. However, heterogeneity in patient selection and definition of treatment response in the existing literature make the application of trial results to real-world practice difficult. With the standardization of trial design, prognostic markers of treatment response can be identified, allowing the selection of patients for the most appropriate anti-tumor therapy. Future studies should also continue to utilize therapeutic agents of different classes to achieve synergistic activity while minimizing toxicity.

Funding Statement

The author(s) declared that no grants were involved in supporting this work.